Propranolol for the treatment of ulcerated infantile hemangiomas: A prospective study

To the Editor: Propranolol has been reported to be successful in the treatment of ulcerated infantile hemangiomas (IHs).1Hermans D.J. van Beynum I.M. Schultze Kool L.J. van de Kerkhof P.C. Wijnen M.H. van der Vleuten C.J. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls.J Am Acad Dermatol. 2011; 64: 833-838Google Scholar, 2Qiu T. Yang K. Dai S. Chen S. Ji Y. Clinical features of segmental infantile hemangioma: a prospective study.Ther Clin Risk Manag. 2021; 17: 119-125Google Scholar, 3Polites S.F. Rodrigue B.B. Chute C. Hammill A. Dasgupta R. Propranolol versus steroids for the treatment of ulcerated infantile hemangiomas.Pediatr Blood Cancer. 2018; 65: e27280Google Scholar The results of these studies are encouraging but inconsistent, and the effect of propranolol therapy on ulcerated IHs is difficult to assess because of the small number and heterogeneity of IHs (eg, proliferating vs involuting) enrolled in the published studies. To test the efficacy and safety of propranolol in this setting, we conducted a prospective, multicenter, phase II trial in patients with proliferating ulcerated IHs. A total of 99 patients were screened for eligibility over a 12-month period, and 85 patients were enrolled (Table I). The mean size of the ulcerations was 4.9 cm2 (standard deviation = 4.8; range, 0.04-25.0 cm2). Propranolol was initiated at a dosage of 1.0 mg/kg per day, divided 3 times daily for 1 week, which was then increased to 2 mg/kg per day, divided 3 times daily from week 2.Table IDemographic and clinical characteristics at baselineCharacteristicsn = 85∗With a 2.5% 1-sided test level, 60 patients had to be recruited to detect a 24-week excellent response rate of 25% or more with 90% power. To account for losses to follow-up and consent withdrawal, we decided to recruit at least 80 patients.Patients Sex†Values are presented as the number (percentage).Female62 (72.9) Age, w‡Values are presented as the mean (range).13.3 (5.0-24.0) Gestational age†Values are presented as the number (percentage).Born prematurely15 (17.6)Infantile hemangiomas Location†Values are presented as the number (percentage).Head and face29 (34.1)Neck, trunk, and extremities56 (65.9) Morphologic subtype†Values are presented as the number (percentage).Localized47 (55.3)Indeterminate7 (8.2)Segmental31 (36.5) Description†Values are presented as the number (percentage).Superficial23 (27.1)Mixed62 (72.9) Lesion size, cm2‡Values are presented as the mean (range).26.9 (1.5-300.0) PHACE syndrome†Values are presented as the number (percentage).§PHACE syndrome: posterior fossa malformations, hemangiomas, arterial malformations, coarctation of the aorta and other cardiac defects, and eye anomalies.Yes3 (3.5)Hemangioma ulceration Age at the discovery of ulceration, w‡Values are presented as the mean (range).7.8 (1.0-19.50) Ulceration size, cm2‡Values are presented as the mean (range).4.9 (0.04-25.0) Prior duration of ulceration, w‡Values are presented as the mean (range).5.5 (1.0-11.0)w, Week.∗ With a 2.5% 1-sided test level, 60 patients had to be recruited to detect a 24-week excellent response rate of 25% or more with 90% power. To account for losses to follow-up and consent withdrawal, we decided to recruit at least 80 patients.† Values are presented as the number (percentage).‡ Values are presented as the mean (range).§ PHACE syndrome: posterior fossa malformations, hemangiomas, arterial malformations, coarctation of the aorta and other cardiac defects, and eye anomalies. Open table in a new tab w, Week. Propranolol treatment resulted in excellent and good responses in 38.8% and 54.1% of patients, respectively, at week 24, with a total response rate of 92.9% (Supplemental Figs 1 to 3 available via Mendeley at https://doi.org/10.17632/ptrrxtn689.1). A logistic regression model for the excellent outcome showed that young age (95% confidence interval, 0.368-0.940; P = .027) and small hemangioma size (95% confidence interval, 0.566-0 .931; P = .012) were independent factors predictive of excellent response (Table II).Table IIBaseline factors predictive of an excellent response at week 24 (logistic regression analysis)∗The treatment outcomes were classified as excellent (compete or nearly complete resolution of the IH), good (partial resolution), stable (no further growth), or deterioration at week 24 versus baseline (week 0) according to the evaluation. The primary outcome measure was the excellent response at 24 weeks in the intention-to-treat population of all patients who were enrolled. Photographs of IHs were taken at weeks 0 and 24. All standardized photographs were reviewed by an independent expert panel.VariablesP value†P < .05 indicates statistically significant difference.Odds ratio95% confidence intervalSex.8100.7940.121-5.196Age.0270.5890.368-0.940Gestational age.4942.1820.234-20.393Hemangioma size.0120.7260.566-0.931Location.3072.2650.471-10.883Morphologic subtype.7091.4990.179-12.544Hemangioma description.4620.5240.094-2.932Age at the discovery of ulceration.0641.5160.976-2.353Ulceration size.2801.1610.886-1.520∗ The treatment outcomes were classified as excellent (compete or nearly complete resolution of the IH), good (partial resolution), stable (no further growth), or deterioration at week 24 versus baseline (week 0) according to the evaluation. The primary outcome measure was the excellent response at 24 weeks in the intention-to-treat population of all patients who were enrolled. Photographs of IHs were taken at weeks 0 and 24. All standardized photographs were reviewed by an independent expert panel.† P < .05 indicates statistically significant difference. Open table in a new tab The complete healing time of the ulceration (CHTU) occurred within 0.5 to 10 weeks of treatment initiation in all patients, with a mean CHTU of 5.5 weeks. The factors influencing the CHTU were hemangioma size (R = 0.360, P = .001, Spearman R coefficient) and ulceration size (R = 0.740, P < .001, Spearman R coefficient). The mean total time of ulceration (TTU) was 9.4 weeks. The TTU correlated significantly and positively with the prior duration of ulceration (R = 0.683, P < .001, Spearman R coefficient). Common adverse events were diarrhea, agitation, sleep disturbance, and vomiting (Supplemental Table I; available via Mendeley at https://doi.org/10.17632/ptrrxtn689.1). Propranolol was permanently discontinued in 1 patient because of severe sleep disturbance. In the present study, propranolol treatment leads to a considerable shortening of the natural course of IHs. We found that young age was positively associated with excellent response in the logistic regression analysis. In the study by Hermans et al,1Hermans D.J. van Beynum I.M. Schultze Kool L.J. van de Kerkhof P.C. Wijnen M.H. van der Vleuten C.J. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls.J Am Acad Dermatol. 2011; 64: 833-838Google Scholar a tendency toward a shorter TTU was seen in patients starting propranolol at an early age. In addition, we found that small hemangioma and ulceration sizes were associated with a short CHTU. Our study revealed that the TTU correlated significantly and positively with the prior duration of ulceration but not the CHTU. The data presented here suggest that the termination of IH proliferation by propranolol might have a direct effect on the duration of ulceration. Our findings reiterated the recommendations that early referral of high-risk patients to IH experts and early treatment with propranolol, whenever possible, are advised to prevent more severe complications.4Ji Y. Chen S. Xiang B. Yang Y. Qiu L. Safety and tolerance of propranolol in neonates with severe infantile hemangiomas: a prospective study.Sci Rep. 2017; 7: 1503Google Scholar A slower dose escalation or a lower maintenance dose of propranolol should be considered in ulcerated IHs. This trial provided new evidence in support of the consensus guidelines that recommend propranolol therapy for ulcerated IHs.5Krowchuk D.P. Frieden I.J. Mancini A.J. et al.Clinical practice guideline for the management of infantile hemangiomas.Pediatrics. 2019; 143: e20183475Google Scholar None disclosed.